Plant-derived extracts regulate immunosuppressive myelopoiesis in Breast cancer patients

植物提取物调节乳腺癌患者的免疫抑制性骨髓细胞生成

• 批准号: 10622036
• 负责人: Paulo Cesar Rodriguez
• 金额: $ 21.06万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622036
• 关键词: Adjuvant; American Indians; Animal Model; Bile Acids; Binding; Breast Cancer Patient; Breast Cancer Treatment; CD8B1 gene; Caesalpinia; Cancer Etiology; Cancer Patient; Caribbean region; Catabolism; Cell Death; Cells; Cessation of life; Chinese; Cholesterol; Clinical; Clinical Research; Colombia; Colombian; Complementary and alternative medicine; Complex; Development; Endoplasmic Reticulum; Flow Cytometry; Foundations; Frequencies; Funding; Gallic acid; Goals; Hindu; Human; Immune; Immune Evasion; Immunity; Immunosuppression; Immunotherapy; Indigenous; Infrastructure; Intestines; Latin American; Link; Liver; Malignant Neoplasms; Mediating; Metabolic; Monitor; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Natural Products; Neoadjuvant Therapy; Neoplasm Metastasis; Parents; Patients; Phase; Phosphotransferases; Placebos; Plant Extracts; Plants; Plasma; Population; Prevention; Primary Neoplasm; Progression-Free Survivals; Proteins; Quality of life; Reaction; Research; Role; Sampling; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; South America; T-Lymphocyte; Technology; Testing; Therapeutic; Treatment Protocols; Tumor Immunity; Validation; antitumor effect; base; cancer cell; cancer immunotherapy; chemotherapy; endoplasmic reticulum stress; granulocyte; immunogenic; interest; low and middle-income countries; malignant breast neoplasm; metabolomics; monocyte; mortality; mouse model; patient population; polyphenol; predicting response; prevent; receptor; response; success; therapeutically effective; transcription factor; treatment response; tumor; tumor growth; tumor microenvironment

ABSTRACT This supplement is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-054. Therapeutic strategies based on traditional, complementary, and alternative medicine (TCAM) have emerged as a potential treatment option for cancer, especially in low- and middle-income countries (LMICs) with limited access to advanced technologies. However, the impact of well-controlled TCAM-based treatments in the modulation of protective anti-tumor immunity in cancer patients remains poorly defined. Expansion of myeloid- derived suppressor cells (MDSC) in tumor-bearing hosts represents a primary mechanism to limit protective anti- tumor T cell immunity and a major obstacle to the success of cancer immunotherapy. It is therefore imperative to develop new effective therapeutic strategies to overcome the immune restricting effects induced by MDSC in tumors. Our recent studies demonstrated that MDSC in tumors activate an integrated signaling network known as the unfolded protein responses (UPR) as a reaction to the sustained and pronounced endoplasmic reticulum (ER) stress induced by the precarious conditions of the tumor microenvironment (TME). Furthermore, conditional deletion of the UPR-related PKR-like ER kinase (PERK) functionally reprogrammed tumor-MDSC into immune- stimulatory cells that partially restore protective anti-tumor immunity. In the related R01, we postulate that the accumulation of Bile Acids (BAs) in tumor-bearing hosts restricts the functional transformation of PERK-ablated MDSC. However, the validation of the BAs and ER stress axis in MDSC in human populations remains unknown. P2Et, a polyphenol-rich extract from plant Caesalpinia spinosa, promotes anti-tumor activities through activation of protective immunity and direct anti-tumor effects, both reducing the frequency of intratumor MDSC. Although P2Et induces anti-tumor actions in animal models, its effect in patient populations remains unknown. In this supplement, we aim to intersect a funded Phase I/II clinical study testing the effect of P2Et in Breast cancer (BC) patients receiving neoadjuvant chemotherapy in Colombia, South America, with R01-linked research testing the effects of MDSC undergoing elevated ER stress activation and alterations in plasma BAs. We hypothesize that patients receiving P2Et as part of their treatment regimen will show reduced numbers of ER-stressed MDSC and lower levels of circulating BAs, which associate with positive therapeutic responses. We propose the following Specific Aims: Aim 1. Evaluate the expansion of circulating MDSC and plasma BAs in stage II-III BC patients undergoing treatment with P2Et plus neoadjuvant therapy. Aim 2. Determine whether alterations in circulating MDSC and plasma BAs predict responses in stage II-III BC patients administered with P2Et. Proposed research will advance the scope of the parent RO1 by potentially elucidating the effects of the ER stress and BAs axis in MDSC from cancer patients, while enabling TCAM-based strategies in LMICs to drive protective immunity, potentially overcoming a substantial obstacle for cancer immunotherapies.

摘要 本补充资料是针对被确认为非CA-CA的特殊利益通知(NOSI)而提交的 22-054。基于传统、补充和替代医学(TCAM)的治疗策略有 成为癌症的潜在治疗选择，特别是在低收入和中等收入国家(LMIC) 获取先进技术的机会有限。然而，控制良好的以TCAM为基础的治疗在 癌症患者保护性抗肿瘤免疫的调节机制仍不明确。髓系扩张- 肿瘤宿主中的衍生抑制细胞(MDSC)是限制保护性抗肿瘤免疫的主要机制。 肿瘤免疫和T细胞免疫是肿瘤免疫治疗成功的主要障碍。因此，这是当务之急 开发新的有效治疗策略以克服MDSC诱导的免疫抑制效应 肿瘤。我们最近的研究表明，肿瘤中的多药耐药干细胞激活了一个已知的整合信号网络 作为对持续的和明显的内质网的反应的未折叠蛋白反应(UPR) (Er)由不稳定的肿瘤微环境(TME)条件引起的应激。此外，有条件的 删除UPR相关的PKR样ER激酶(PERK)功能性地将肿瘤MDSC重新编程为免疫-MDSC 部分恢复保护性抗肿瘤免疫的刺激细胞。在相关的R01中，我们假设 胆汁酸(BAS)在荷瘤宿主体内的蓄积限制了经PERK消融术后的功能转化 MDSC。然而，人类MDSC中bas和内质网应力轴的有效性仍不清楚。 P2Et是一种富含多酚的刺苏子提取物，通过激活促进抗肿瘤活性 保护性免疫和直接抗肿瘤作用，两者都减少了肿瘤内MDSC的频率。虽然 P2Et在动物模型中诱导抗肿瘤作用，其在患者群体中的作用尚不清楚。在这 补充，我们的目标是交叉资助的I/II期临床研究，测试P2Et在乳腺癌(BC)中的作用 在南美洲哥伦比亚接受新辅助化疗的患者，与R01相关的研究测试 内质网应激激活对MDSC的影响及血浆BAs的变化。我们假设 接受P2Et作为治疗方案一部分的患者将显示内质网应激MDSC数量减少和 循环中bas水平较低，这与积极的治疗反应有关。我们提出以下建议 具体目标：目标1.评估II-III期BC患者循环MDSC和血浆BAS的扩张性 接受P2Et加新辅助治疗。目标2.确定循环中的变化是否 MDSC和血浆bas可预测接受P2Et治疗的II-III BC期患者的反应。建议的研究 将通过潜在地阐明内质网应激和基础轴的影响来推进亲代RO1的范围 来自癌症患者的MDSC，同时使基于TCAM的策略在LMIC中促进保护性免疫， 有可能克服癌症免疫疗法的重大障碍。